提高基因组稳定性对于延缓细胞衰老十分重要。作为哺乳动物SIRTUIN家族的一员，SIRT6是能延长不同低等生物寿命的Sir2的同源基因。证据显示SIRT6通过调控基因组稳定性延缓小鼠衰老。我们构建了检测DNA双链断裂修复和核苷酸切除修复的模型，并利用它们证明在人正常细胞中SIRT6不仅通过单ADP核糖化PARP1提高DNA双链断裂修复效率，也通过不依赖于PARP1的通路促进核苷酸切除修复。此外，小泛素修饰蛋白Sumo3能够修饰SIRT6并提高其稳定性，但其是否参与调控基因组稳定性尚未被研究。为了深入阐明SIRT6调控基因组稳定性的分子机制，我们将在细胞水平上进一步研究SIRT6调控DNA双链断裂修复和核苷酸切除修复的机制，探索SIRT6翻译后修饰如小泛素化对基因组稳定性调控的影响，并利用已构建完善的研究DNA修复的小鼠模型在动物水平上探索SIRT6调控上述两条通路的机制。

Maintenance of genomic stability is of great importance to prevent cells from entering senescent state. Emerging evidence indicates that SIRT6, a mammalian homolog of Sir2 that extends lifespan in various orgainisms including yeast, nematode and fruit fly, participates in suppressing genomic instabilty, helping improve mouse lifespan. We created sensitive and quantitative assays to measure efficiency of different types of DNA repair including DNA double strand break repair (DSB repair) and nucleotide excision repair (NER) based on green fluorescent protein. With these powerful tools, we found SIRT6 stimulates DNA DSB repair by mono-ADP-ribosylating PARP1, an important repair protein involved in various types of DNA repair. In addition, we also found that SIRT6 enhances NER, but it is independent of PARP1. Moreover, our data shows that SIRT6 is modified by Sumo3, leading to the improvement of SIRT6 stability. To further elucidate molecular mechanisms of regulating genomic stability by SIRT6, based on our preliminary data, we plan to study the following projects. Aim 1: To further investigate roles of SIRT6 in regulating DNA DSB repair, particularly classical nonhomologous end joining (C-NHEJ) pathway. Aim 2: To elucidate the molecular mechanisms of regulating NER by SIRT6. We will mainly focus on identifying new candidate proteins which mediate the regulation of NER by SIRT6. Aim 3: To examine roles of SIRT6 sumoylation in maintaining genomic stablity. Aim 4: To test functional roles of SIRT6 in DNA repair using in vivo mouse models.